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TRIENNIAL GROWTH SYMPOSIUM |
Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle 98195, and Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA 98108
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Abstract |
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, resistin, and adiponectin have been shown to affect muscle metabolism, protein dynamics, or both, by direct actions. This review summarizes recent results that support the existence of a reciprocal muscle-to-fat signaling pathway involving release of the cytokine IL-15 from muscle tissue. Cell culture studies, short-term in vivo studies, and human genotype association studies all support the model that muscle-derived IL-15 can decrease fat deposition and adipocyte metabolism via a muscle-to-fat endocrine pathway. Fat:lean body composition is an important factor determining the efficiency of meat production, as well as the fat content of meat products. Modulation of the IL-15 signaling axis may be a novel mechanism to affect body composition in meat animal production.
Key Words: skeletal muscle • adipose tissue • body composition • cytokine • interleukin-15 • protein degradation
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INTRODUCTION |
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). Since that time, several more adipose-derived hormonal factors, termed adipokines, which regulate body composition, have been discovered (Trayhurn and Wood, 2004). Adipokines exclusively or primarily produced by adipose tissue include leptin, resistin, and adiponectin (Trujillo and Scherer, 2006). Although not the exclusive source, adipose tissue also secretes tumor necrosis factor- (TNF-) and IL-6 (Trujillo and Scherer, 2006). These factors have direct effects on skeletal muscle mass and physiologic activities (Reid and Li, 2001; Dyck et al., 2006). A reciprocal signaling pathway, in which factors secreted by skeletal muscle tissue affect adipose tissue metabolism, has not been definitively identified.
This review will summarize recent results that support the existence of a muscle-to-fat signaling pathway involving release of the cytokine, IL-15, from muscle tissue. Interleukin-15 is a 14-kDa cytokine first reported by Grabstein et al. (1994). Although originally isolated by its ability to support natural killer (NK) T-lymphocyte proliferation, a major site of IL-15 transcription is skeletal muscle (Grabstein et al., 1994; Tagaya et al., 1996; Fehniger and Caligiuri, 2001). Cell culture and short-term in vivo experiments have indicated that IL-15 inhibits skeletal muscle protein degradation (Carbó et al., 2000; Quinn et al., 2002; Busquets et al., 2005). Additionally, IL-15 has direct actions on cultured adipocytes (Ajuwon and Spurlock, 2004; Quinn et al., 2005) and decreases fat deposition in vivo in rodent models (Carbó et al., 2001; Alvarez et al., 2002). These findings indicate that IL-15 may be secreted from skeletal muscle and function as an endocrine regulator of adipose tissue, thus acting as a myokine (Pedersen and Fischer, 2007).
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IL-15 PROTEIN AND EXPRESSION PATTERN |
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; Budagian et al., 2006). However, IL-15 is classified as a cytokine by its secondary structure, a 4-helix bundle similar to other cytokines such as IL-2 and IL-6 (Waldmann and Tagaya, 1999; Fehniger and Caligiuri, 2001). This structural family of proteins is also known as class-I helical cytokines, or the helix bundle peptide family, and includes many IL, as well as GH, leptin, and erythropoietin (Horseman and Yu-Lee, 1994; Huising et al., 2006). Members of this protein family have similar secondary structures and bind to receptors with similar structures (Horseman and Yu-Lee, 1994; Huising et al., 2006). Interleukin-15 signals via a heterotrimeric receptor with 2 of the 3 subunits shared with other cytokines (Tagaya et al., 1996; Fehniger and Caligiuri, 2001; Budagian et al., 2006). Interleukin-15 has been cloned from human, mouse, bovine, porcine, feline, and rabbit genomes, with 70 to 80% homology among these species (Budagian et al., 2006). Chicken IL-15 has also been cloned, with considerably less homology to IL-15 in mammalian species (Choi et al., 1999). However, mammalian and avian IL-15 have similar patterns of expression and in vitro activity, suggesting similar functions (Choi et al., 1999; Budagian et al., 2006). Whether avian IL-15 has actions in fat and muscle tissue has not been described.
Interleukin-15 has numerous immune-related functions, as well as antiapoptotic and anti- and proinflammatory actions in many tissues (Budagian et al., 2006). At the mRNA level, IL-15 has wide tissue distribution in mammals, being expressed in lymphoid tissues as well as skeletal muscle, placenta, heart, lung, liver, kidney, brain, and testis (Tagaya et al., 1997; Satoh et al., 1998). Interleukin-15 expression has not been described in adipose tissue, and reports on the presence of IL-15 mRNA expression by cultured adipocytes are conflicting and are reviewed subsequently.
The posttranslational regulation of IL-15 is complex, but the major site of IL-15 mRNA transcription and probable secretion of IL-15 is skeletal muscle tissue (Grabstein et al., 1994; Tagaya et al., 1997). At the protein level, IL-15 has been immunolocalized to human skeletal muscle fibers in tissue sections that contained few IL-15-positive infiltrating cells (Sugiura et al., 2002). Interleukin-15 mRNA and biologically active IL-15 protein are expressed in primary human myogenic cultures (Sugiura et al., 2002) and human rhabo-domyosarcoma-derived cell lines (Lollini et al., 1997). Interleukin-15 mRNA abundance is low, but detectable, in mouse C2C12 skeletal myogenic cultures at the myoblast stage but is induced about 10-fold upon differentiation (Quinn et al., 2005). Therefore, published evidence indicates that IL-15 is expressed by skeletal muscle fibers themselves, not vascular, connective tissue or lymphoid-infiltrating cells present in muscle and in primary cultures. This point is significant in light of recent evidence that many of the proinflammatory factors secreted from adipose tissue are, in fact, derived from immune-infiltrating cells such as macrophages rather than adipocytes (Weisberg et al., 2003; Xu et al., 2003; Trayhurn and Wood, 2004). These results support the hypothesis that IL-15 plays an autocrine or paracrine role in modulation of skeletal muscle metabolism, growth, and (or) adaptation.
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IL-15 mRNA ISOFORMS |
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, 1997; Fehniger and Caligiuri, 2001). Believed to be transcribed from alternative promoters, the 2 isoforms differ in the lengths of the signal peptides and are designated long signal peptide (LSP) and short signal peptide (SSP)-IL-15 mRNA (Tagaya et al., 1996, 1997). Identical mature proteins are encoded by SSP-and LSP-IL-15 mRNA (Tagaya et al., 1997), but these isoforms differ in tissue expression patterns and intracellular trafficking (Tagaya et al., 1996; Fehniger and Caligiuri, 2001; Budagian et al., 2006). Short signal peptide-IL-15 mRNA is highly transcribed in heart and also expressed in thymus, testes, and appendix, whereas LSP-IL-15 mRNA is transcribed strongly in skeletal muscle and placenta and at lower levels in heart, lung, liver, thymus, and kidney (Tagaya et al., 1996, 1997; Fehniger and Caligiuri, 2001; Budagian et al., 2006).
Short signal peptide-IL-15 does not appear to be secreted and either functions intracellularly or is released after cell damage (Tagaya et al., 1996, 1997; Fehniger and Caligiuri, 2001). Long signal peptide-IL-15 is secreted; however, the unusually long 48-AA signal peptide renders IL-15 secretion extremely inefficient (Tagaya et al., 1996, 1997; Fehniger and Caligiuri, 2001). Interleukin-15 protein expression is also regulated at the translational level (Tagaya et al., 1996, 1997; Fehniger and Caligiuri, 2001). Multiple AUG (i.e., initiation codons) in the 5' untranslated region impede LSP-IL-15 translation efficiency (Tagaya et al., 1996, 1997; Fehniger and Caligiuri, 2001). Because of the blocks to translation and secretion, many studies have shown that even in tissues or cell types that express the LSP-IL-15 mRNA isoform, little correlation exists between mRNA levels and secretion of IL-15 protein (Tagaya et al., 1996, 1997; Meazza et al., 1997; Stoeck et al., 1998; Fehniger and Caligiuri, 2001). Interleukin-15 protein has been difficult to detect in biological fluids and tissues. This may be due to the aforementioned translational blocks (Bamford et al., 1998) and inefficient secretion (Fehniger and Caligiuri, 2001). However, others (Bulfone-Paus et al., 2006; Bulanova et al., 2007) have speculated this difficulty is due to the presence of soluble and cell surface-associated IL-15 receptors (reviewed subsequently). Importantly, human skeletal muscle-derived cultures (Sugiura et al., 2002) and human serum (Riechman et al., 2004) are among the few nonpathologic (or genetically enhanced) instances in which IL-15 protein has been detected, suggesting this is due to high expression of the LSP-IL-15 mRNA isoform, and thus IL-15 secretion, by skeletal muscle. Increased efficiency of IL-15 translation in skeletal muscle compared with other tissues is also possible but has not been examined in detail.
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IL-15 RECEPTOR SUBUNITS |
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cytokine receptor (c), the IL-2 β receptor subunit (IL-2Rβ), and an IL-15-specific receptor (IL-15R; Tagaya et al., 1996; Fehniger and Caligiuri, 2001; Budagian et al., 2006). The 2 signaling subunits, c and IL-2R β, also form receptors for other cytokines (Grabstein et al., 1994; Tagaya et al.,1996; Fehniger and Caligiuri, 2001). Interleukin-15 specificity and high affinity binding are conferred by the IL-15-specific but nonsignaling IL-15R subunit, which is structurally similar (but not homologous) to the receptor subunit of IL-2 (Tagaya et al., 1996; Fehniger and Caligiuri, 2001; Schluns et al., 2005; Bulfone-Paus et al., 2006). The 3 IL-15 receptor subunits are widely expressed at the mRNA level in many tissues. Rodent skeletal muscle (Pistilli et al., 2007) and white adipose tissue (Alvarez et al., 2002) express mRNA for all 3 IL-15 receptor subunits, suggesting this receptor complex is functional in muscle and fat.
The molecular genetics of the IL-15R are complex, because IL-15R has numerous isoforms due to alternative splicing (Schluns et al., 2005; Budagian et al., 2006). In addition to participating in the heterotrimeric signaling complex described previously, the IL-15R can also appear in soluble forms (sIL-15R) that can either inhibit or potentiate IL-15 activity (Bulanova et al., 2007). One sIL-15R isoform derived by differential splicing acts as an agonist, whereas a slightly different sIL-15R form generated by proteolytic cleavage at the cell surface acts as an antagonist (Rubenstein et al., 2006; Bulanova et al., 2007). The IL-15R can also appear on cell surfaces independently from the c and IL-2Rβ, in which case it is believed to present IL-15 to adjacent cells expressing the c-IL-2Rβ heterodimer in a juxtacrine mode of action (Budagian et al., 2006; Bulfone-Paus et al., 2006). Another splice variant of IL-15R lacks the exon 2-encoded IL-15 binding domain but retains the ability to bind to the c-IL-2Rβ dimer, thus inhibiting the ability of the complex to bind IL-15 and transduce signal (Schluns et al., 2005). The IL-15R also can form intracellular complexes with the nonsecreted isoform of IL-15 (i.e., SSP-IL-15), and evidence indicates that this complex can translocate to the nucleus and repress IL-15 expression (Nishimura et al., 2005). It is unclear how differential splicing of the IL-15R gene is controlled, but it appears that different cell populations tend to generate specific splice variants (Bulfone-Paus et al., 2006). The IL-15R forms expressed by skeletal myogenic and adipogenic cells in different physiologic conditions have not been characterized.
Intriguingly, 2 studies of genetic variation in human subjects have identified SNP in the human IL-15R that correlate with either muscle or fat deposition in humans. One study (Riechman et al., 2004) showed that 2 separate SNP in exons 4 and 7 of the human IL-15R gene correlated strongly with the degree of muscle hypertrophy in response to a regimen of resistance exercise training. Another study, by a different group, found 2 highly linked IL-15R SNP, 1 in the same area as the exon 4 polymorphism identified by Riechman et al. (2004), and 1 at the border of exon 5 and intron 5, which correlated negatively with percentage of body fat (Di Renzo et al., 2006). These findings indicate that the complex regulation of IL-15R splicing could have been affected by these SNP, which in turn regulated IL-15 signaling or availability in human subjects. These findings strongly indicate that IL-15 plays an important role in the regulation of fat:lean body composition in humans and possibly in other mammalian species.
As discussed previously, white adipose tissue harvested from mice and rats possesses mRNA for all 3 IL-15 receptor subunits (Alvarez et al., 2002). Further, transcription of mRNA for the 2 signaling subunits of the IL-15 receptor is downregulated in obese Zucker rats, correlating with a lack of effect of IL-15 on adipose tissue in obese, but not lean, rats (Alvarez et al., 2002). Interleukin-15 receptor expression has not been completely characterized in skeletal muscle nor in adipose tissue in response to different physiologic states such as caloric excess, caloric restriction, insulin resistance, sepsis, or inflammation. Given the complex regulation of different IL-15R isoforms, their different functions, and the correlation of human IL-15R SNP with body composition, it is possible that changes in the expression or ratios of the different subunits of the IL-15 in different physiological states could modulate IL-15 responsiveness in muscle and adipose tissue.
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IL-15 ACTIONS IN OTHER TISSUES |
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). Because of the similar effects of IL-15 and IL-2 on NK-like cell lines, as well as structural similarities and the sharing of 2 receptor subunits (i.e., c and IL-2Rβ), the actions of IL-15 and IL-2 were originally thought to be similar. However, although IL-2 is primarily expressed by activated T-cells, IL-15 has much broader tissue expression and actions (Tagaya et al., 1996). Interleukin-15 has been ascribed numerous functions in both adaptive and innate immunity, such as generation of memory CD8+ cells, 
T cells, NK T cells, some kinds of B cells, and some subsets of intraepithelial lymphocytes (Waldmann and Tagaya, 1999; Fehniger and Caligiuri, 2001). Interleukin-15 also stimulates immune activities in eosinophils, neutrophils, mast cells, monocytes, and macrophages (Budagian et al., 2006).
Interleukin-15 has both pro- and antiinflammatory functions in various tissues and disease states. For example, IL-15 expression is correlated with inflammation in rheumatoid arthritis and inflammatory bowel disease (McInnes et al., 1997; Vainer et al., 2000). However, recent data indicated IL-15 is protective of intestinal epithelial cells and thus may function to counteract bowel inflammation (Obermeier et al., 2006). Interleukin-15 also has antiinflammatory and antiapoptotic activity in a murine model of nephritis (Shinozaki et al., 2002) and prevents the progression of murine retrovirus-induced acquired immunodeficiency syndrome (Umemura et al., 2002). Interleukin-15 has potent anti-apoptotic activity in many tissues (Budagian et al., 2006). In a mouse model of Escherichia coli-induced shock, IL-15 inhibited TNF--induced apoptosis in numerous tissues and protected from septic shock (Hiromatsu et al., 2003). Some in vitro evidence indicates that the activated IL-15R directly inhibits TNF- signaling by competing with the type-1 TNF- receptor for a specific adaptor protein (Bulfone-Paus et al., 1999). This is significant to scientists interested in muscle biology, in light of the strong evidence that TNF- functions to stimulate skeletal muscle proteolysis and apoptosis, and thus is implicated in cachexia and age-associated muscle wasting (Reid and Li, 2001; Dirks and Leeuwenburgh, 2006).
Interleukin-15 and IL-15R mRNA are expressed in many other tissues, including the brain, where they appear to stimulate non-rapid eye movement sleep (Kubota et al., 2001). Interleukin-15 has also been reported to have proangiogenic activity (Angiolillo et al., 1997). Finally, a short report from an Italian group (Gangemi et al., 2005) suggested that humans who lived independently beyond age 95 had unusually high serum IL-15 concentrations compared with unselected elderly and middle-aged subjects, suggesting this was a preexisting protective factor for the long-lived individuals. The authors speculated that the elevated IL-15 levels supported improved immune function in these individuals, leading to enhanced longevity, although other physiologic variables, such as muscle strength, fat mass, cardiovascular health, and insulin sensitivity, could have been affected as well.
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IL-15 ACTIONS IN SKELETAL MUSCLE |
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demonstrated that recombinant IL-15 increased contractile protein accretion in mouse myogenic cell lines and in primary bovine skeletal myogenic cultures. The hypertrophic effect of IL-15 was not associated with stimulation of myoblast proliferation. In the case of the primary bovine myogenic cultures, pure differentiated myotubes could be generated by use of the mitotic poison aphidicolin; in such cultures, addition of 10 ng/mL of recombinant IL-15 doubled myosin heavy chain accretion and was as effective as IGF-I administered at 10 or 100 ng/mL. Further work, using a retroviral vector to overexpress IL-15 in the mouse C2 skeletal myogenic cell line, indicated IL-15 had little effect on myoblast proliferation and differentiation, instead acting directly on differentiated myotubes to modulate skeletal muscle protein dynamics (Quinn et al., 2002). The C2 myotubes which overexpressed IL-15 exhibited greater rates of protein synthesis and lower rates of protein degradation, resulting in markedly increased accretion of myofibrillar proteins and a hypertrophic morphology (Quinn et al., 2002). Thus, direct action of IL-15 on muscle fibers is in contrast to the principal hypertrophic actions of IGF-I and -II, which involve stimulation of myoblast proliferation and differentiation (Florini et al., 1996). These findings on the difference between IL-15 and IGF-I action were extended to primary human skeletal myogenic cultures (Furmanczyk and Quinn, 2003).
However, in a cell culture study in which IGF-I and -II effects were inhibited by overexpression of IGF binding protein-4 (IGFBP-4), IL-15 was able to stimulate skeletal myoblast differentiation in IGFBP-4 transfected (but not parental) myogenic cultures (Quinn et al., 1997). These observations suggest that IL-15 may affect skeletal myoblast or muscle satellite cell activities in physiological conditions in which IGF-I concentrations are low, such as aging, cancer, or sepsis (Lamberts et al., 1997; Frost and Lang, 2003; Costelli et al., 2006). Intriguingly, cell lines derived from human rhabdomyo-sarcomas (skeletal muscle tumors), which exhibit depressed differentiation, express IL-15 mRNA, secrete detectable levels of IL-15, and express the IL-15R but not the other 2 subunits of the receptor (Lollini et al., 1997), indicating that IL-15 may be functionally sequestered in these tumors.
In vivo experiments generally confirmed cell culture experiments that indicated that IL-15 can modulate skeletal muscle protein dynamics. Carbó et al. (2000), using daily s.c. injections of recombinant human IL-15 into laboratory rats, observed that IL-15 inhibited muscle protein breakdown but did not increase muscle protein synthetic rates. In healthy, growing rats, IL-15 administration induced more than 3-fold decreases in muscle proteolysis rates, associated with a slight depression in muscle protein synthetic rates. Only small increases (which were not significant for most muscles) in muscle weight and protein accretion were observed (Carbó et al., 2000). However, in rats implanted with cachexia-inducing tumors, which greatly increased muscle proteolysis, IL-15 administration resulted in close to 10-fold decreases in the rate of muscle protein degradation and significant preservation of muscle weight and protein content compared with tumor-bearing rats treated only with saline vehicle (Carbó et al., 2000). In a similar study by the same group, IL-15 administration suppressed apoptosis of skeletal muscle nuclei associated with cancer cachexia (Figueras et al., 2004). Interleukin-15 also reduced expression of TNF- receptors and inducible NO synthase, indicating that IL-15 can inhibit TNF--induced muscle protein degradation and apoptosis. Similar results (inhibition of pro-teolysis but no effect on protein synthesis) were observed by Busquets et al. (2005), who studied the effect of IL-15 on protein dynamics in isolated rat muscle preparations. Recombinant IL-15 administration by osmotic pumps also improved diaphragm muscle strength and muscle fiber area and decreased muscle fibrosis in a mouse model of muscular dystrophy, while again having no effect on nondystrophic (normal) mice (Harcourt et al., 2005). It was also observed that IL-15 had minimal effects on muscle regeneration, a myoblast-dependent event (Harcourt et al., 2005).
Taken together, in vivo studies indicate IL-15 has limited ability to stimulate muscle growth in healthy animals. However, IL-15 appears to have the ability to stabilize skeletal muscle protein in pathological situations characterized by muscle protein breakdown and myonuclear apoptosis. Because TNF- is associated with both of these processes, it is tempting to speculate that IL-15 action in skeletal muscle may be mediated by its ability to inhibit TNF- signaling (Bulfone-Paus et al., 1999). However, this mechanism has not been tested in skeletal muscle tissue or cultures. Agricultural animals are often subjected to suboptimal husbandry conditions, including temperature stress and infection; thus, modulation of IL-15 signaling pathways may be a future strategy to preserve muscle mass in such situations.
The difference between the effects of IL-15 in vivo and in vitro also indicates that some control on the effects of IL-15 on muscle protein synthesis, which exists in vivo, is absent in the skeletal myogenic culture models. One such control could be muscle fiber protein to DNA ratios, which in cultured myotubes are far below that of muscle fibers, even in developing animals. Thus, in cultured cells, IL-15 may be able to stimulate muscle protein synthesis, as well as inhibit protein breakdown, because muscle protein accretion is not limited by DNA content.
As mentioned above, Riechman et al. (2004) showed that genetic variability in the human IL-15R correlated with the degree of muscle hypertrophy developed in response to a 10-wk program of resistance exercise training. Two SNP in the IL-15R accounted for approximately 10% of the variation in hypertrophy in response to the training regimen. Muscle quality (strength-limb circumference) in these groups was lower; however, total increases in strength were greater because of the increase in limb circumference. Taken together, these results support the hypothesis that IL-15 plays a role in skeletal muscle hypertrophy in human subjects and possibly in other large mammalian species.
Interleukin-15 may modulate other aspects of skeletal muscle metabolism besides protein dynamics. Interleukin-15 stimulates lipid oxidation in isolated skeletal muscles and in liver (Almendro et al., 2006). Interleukin-15 also increased glucose uptake into skeletal muscle in vitro and in isolated rat muscles (Busquets et al., 2006).
Mice with targeted deletion of the IL-15 gene lack NK cells and exhibit low numbers of other IL-15-dependent immune cells but show little difference in weight or skeletal muscle histology compared with wild-type mice (Kennedy et al., 2000). Mice lacking the IL-15R similarly exhibited immune cell deficiencies, but no differences in muscle mass were reported (Lodolce et al., 1998). However, these mice have not been stressed with exercise protocols, over- or under-nutrition protocols, or followed to advanced ages. Like many transgenic knockout mouse lines that show no phenotype unless stressed (Treuting et al., 2002), it is possible that these mouse lines may reveal physiologic roles for IL-15 signaling in conditions other than normal laboratory husbandry.
Little information exists on the control of IL-15 expression and secretion in muscle tissue. The most consistent findings reported are that muscle IL-15 expression, at least at the mRNA level, is modulated by advanced age and muscle activity. Pistilli et al. (2007) found that IL-15 mRNA was elevated in both slow- and fast-aging rat muscles and in the aging quail patagialis muscle. The same study found that IL-15 mRNA was elevated in atrophied slow soleus muscles of young rats but not in the fast plantaris muscle. An effect of aging and immobilization recovery on IL-15 mRNA in rat muscles was also reported by Pattison et al. (2003). However, given the complex regulation of IL-15 translation and secretion described previously, it is unclear whether these changes in IL-15 mRNA transcription reflect similar changes in muscle IL-15 protein expression and secretion in these physiological states. Using strength-trained human subjects, Nieman et al. (2004) observed no changes in muscle IL-15 mRNA after 2 h of intensive weight training. However, Riechman et al. (2004) showed plasma IL-15 protein levels from both untrained and 10-wk-trained human subjects were increased acutely by whole-body resistance exercise and speculated that IL-15 was released after exercise via microtears in muscle fibers. Confirmation that the increase in serum IL-15 was indeed from skeletal muscle is needed, probably in an animal model. In contrast, Ostrowski et al. (1998) observed no changes in plasma IL-15 after 2 h of treadmill running by 2 male athletes. It is unclear if the differences among these studies was due to the use of highly trained vs. relatively untrained athletes or to the difference between aerobic vs. resistance exercise.
Sporadic reports of other hormonal and nutritional factors that affect muscle IL-15 mRNA transcription and circulating IL-15 protein levels have appeared. Using elderly human male subjects, Lambert et al. (2004) administered the synthetic progestin megestrol acetate at 800 mg/d for 12 wk, with or without testosterone (100 mg/wk), resistance training, or the combination of resistance training and testosterone. Progestin ingestion, but no other treatment, caused highly significant increases in circulating IL-15 levels, but this treatment did not correlate with changes in muscle mass or body composition. Sun and Zemel (2007) showed that, in conjunction with an obesigenic diet, high dietary Ca significantly stimulated IL-15 mRNA transcription in both visceral fat and skeletal muscle tissue in a mouse strain highly susceptible to oxidative stress. The authors interpreted this as an increase in antiinflammatory cytokine expression due to Ca-mediated inhibition of 1,25-dihydroxyvitamin D3, thus inhibiting oxidative stress and fat deposition. In myogenic cell cultures, overexpression of an orphan nuclear hormone receptor, retinoid-related orphan receptor , that is highly expressed in muscle, upregulated both IL-15 and myogenin mRNA, as well as several genes that regulate lipid and carbohydrate metabolism, insulin sensitivity, and reactive O2 species (Raichur et al., 2007). Stegall and Krolick (2000) found that rat myocytes upregulated IL-15 mRNA in response to interferon- and the antiinflammatory cytokine IL-4. Finally, using primary human myoblast cultures, Sugiura et al. (2002) found that both intracellular and secreted IL-15 protein were dose-dependently stimulated by several inflammatory mediators, including interferon-, IL-1, IL-1β, TNF-, and lipopolysaccharide (LPS).
Taken together, all of these studies indicate that muscle IL-15 expression is modulated by inflammation, oxidative stress, or both, and support the in vivo and in vitro studies reviewed here indicating that IL-15 plays a role in lipid metabolism and insulin sensitivity. However, because most of these studies measured only IL-15 mRNA, it is unclear if such changes were accompanied by changes in IL-15 protein production or secretion from muscle tissue. Clearly, delineation of muscle IL-15 expression at each level, that is, mRNA, protein, and secretion, in different physiological states is necessary in future studies.
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IL-15 ACTIONS IN ADIPOSE TISSUE |
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), it was noticed that even in healthy (non-tumor-bearing) growing rats, IL-15 administration resulted in approximately 33% reductions in white adipose tissue deposition, with no change in food intake. This observation was followed by a more detailed investigation of the effects of IL-15 administration on lipid metabolism in rats, which confirmed the above findings of highly significant decreases in fat deposition without affecting food consumption (Carbó et al., 2001). This study indicated that IL-15 caused significant reductions in lipoprotein lipase activity and the rate of lipogenesis in white adipose tissue and liver but no change in lipolysis rate in adipose tissue (Carbó et al., 2001). However, working with primary porcine adipocytes, Ajuwon and Spurlock (2004) found that IL-15 dose-dependently stimulated lipolysis and was a much more potent inducer of acute lipolysis than TNF-, IL-6, or LPS. Additionally, this study found that IL-15 had a small inhibitory effect on lipogenesis. In 3T3-L1 adipogenic cell cultures, IL-15 inhibited preadipocyte differentiation and also dose-dependently stimulated secretion of the insulin sensitizing hormone, adiponectin, from differentiated adipocytes (Quinn et al., 2005). These findings clearly indicate that IL-15 has direct actions on adipocytes and lipid metabolism. Discrepancies among studies concerning the effects of IL-15 on lipolysis and lipogenesis could be due to differences between in vivo and in vitro systems, the time frames of these studies, or differences between species and thus need further investigation.
Interleukin-15 inhibited fat deposition in both wild-type and leptin-deficient obese (ob/ob) mice (Alvarez et al., 2002). However, as mentioned previously, recombinant IL-15 administration to lean Zucker rats also inhibited fat deposition but was unable to inhibit fat deposition in leptin receptor-deficient obese (fa/fa) Zucker rats (Alvarez et al., 2002). Obese, but not lean, Zucker rats exhibited significant decreases in expression of mRNA for the c and IL-2Rβ subunits of the IL-15 receptor, whereas expression of mRNA for IL-15R was unchanged. This observation suggests adipose tissue of obese Zucker rats failed to respond to IL-15, because disequilibrium of receptor subunits resulted in uncomplexed IL-15R performing an inhibitory role.
Using highly sensitive real-time PCR, Quinn et al. (2005) found that cultured mouse 3T3-L1 adipogenic cells did not express IL-15 mRNA at any stage of differentiation. In contrast, using RNase protection assays, Ajuwon et al. (2003) found that primary pig adipocytes expressed low levels of IL-15 mRNA, which were upregulated after stimulation with interferon-. Whether IL-15 protein was produced or released into the culture medium was not determined. Further, as discussed previously, differences in immune regulation of adipose tissue metabolism between rodents and swine are possible. Therefore, whether adipose tissue can express IL-15 at the protein level in basal conditions or in immune challenge in various species remains unclear.
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CONCLUSIONS |
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gene that significantly modulates muscle and fat deposition in humans indicates the IL-15 axis plays an important role in the control of fat:lean body composition. Skeletal muscle is a major site of IL-15 mRNA and protein production, and IL-15 expression in muscle cells is stimulated by inflammatory mediators such as interferon-, LPS, and TNF-. Thus, as suggested by Ajuwon and Spurlock (2004), IL-15 may be produced by organisms in response to immune stress to stabilize muscle protein and oxidize fat for energy production. This review has also summarized the existence of several impediments to IL-15 transcription, translation, secretion, and signal transduction, which serve to limit IL-15 action temporally. Therefore, the actions of IL-15 on muscle and fat mass might be exploited in animal production, human medicine, or veterinary medicine by prolonging IL-15 secretion or improving the availability of IL-15 for signaling. However, because the actions and regulation of IL-15 and the IL-15R are complex and possibly differ among species, much more basic research is needed to identify and implement such a strategy.
The literature reviewed here suggests, but does not prove, that muscle-derived IL-15 is secreted into the circulation and acts on other tissues such as adipose tissue, thus constituting a myokine, or muscle-derived endocrine factor. More work is needed to confirm this hypothesis. Other factors, including IL-6 (Pedersen and Fischer, 2007) and myostatin (McPherron and Lee, 2002) have recently been proposed as circulating myokines that regulate fat:lean body composition, although IL-6 and myostatin are also expressed by adipose tissue (McPherron and Lee, 2002; Ajuwon et al., 2003). Further, both Hevener et al. (2003) and Engler (2007) have postulated the existence of uncharacterized myokines that modulate insulin sensitivity and other metabolic parameters. Thus, there is increasing acceptance that myokines play a role in control of body composition and metabolism, and more myokines are likely to be discovered in the future. Interleukin-15 may be one of the first such myokines to be characterized and, as such, opens the door to an exciting new field of inquiry in muscle biology, with the potential to devise new strategies to improve body composition and feed efficiency and to combat muscle wasting associated with stress or immune challenge in agricultural species.
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Footnotes |
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2 Presented at the Triennial Growth symposium at the annual meeting of the American Society of Animal Science, San Antonio, TX, July 8 to 12, 2007.
3 Corresponding author: quinnL{at}u.washington.edu
Received for publication July 25, 2007. Accepted for publication August 16, 2007.
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  L. S. Quinn, B. G. Anderson, L. Strait-Bodey, A. M. Stroud, and J. M. Argiles Oversecretion of interleukin-15 from skeletal muscle reduces adiposity Am J Physiol Endocrinol Metab, January 1, 2009; 296(1): E191 - E202. [Abstract] [Full Text] [PDF]
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Abstract
INTRODUCTION